Adjuvant Everolimus in Non–Clear Cell Renal Cell Carcinoma

Key Points Question Does adjuvant everolimus improve recurrence-free and overall survival in patients with localized non–clear cell renal cell carcinoma (RCC)? Findings This secondary analysis of a randomized clinical trial subgroup included 109 patients with papillary RCC and 99 patients with chromophobe RCC. In both groups, patients treated with adjuvant everolimus did not experience an improvement in recurrence-free survival compared with patients treated with placebo. Meaning In this randomized clinical trial subset analysis, everolimus was not found to significantly improve either outcome when used in the adjuvant setting.


Introduction
4][5][6] The phase 3 randomized clinical trial (RCT), EVEREST, assessed the mammalian target of rapamycin (mTOR) pathway inhibitor, everolimus, in the adjuvant setting. 7In this study, we present a subgroup analysis from this RCT, in which our objective was to identify benefit (if any) from this drug in the papillary and chromophobe RCC subgroups.

Methods
This RCT was a prespecified secondary analysis of the EVEREST RCT.The trial protocol was approved by all participating institutions' institutional review boards and the National Cancer Institute (NCI) central institutional review board, and all participants provided written informed consent.The trial protocol and statistical analysis plan are provided in Supplement 1.This study is reported following the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Trial Design and Participants
EVEREST was a phase 3, double-blind, placebo-controlled RCT. 7Between April 1, 2011, and September 15, 2016, a total of 1545 patients were enrolled across 398 sites in the US.Eligible patients included those with clear-cell and non-clear cell histologies (excluding those with collecting duct or medullary carcinomas).We conducted a subgroup analyses among 109 patients with papillary RCC and 99 patients with chromophobe RCC (eFigure in Supplement 2).
Eligible patients had to have a full surgical resection with negative margins (radical or partial nephrectomy) within 84 days prior to randomization and not in receipt of any other systemic therapy.Additionally, patients were required to either be categorized as intermediate-high risk for recurrence (tumor stage 1B with grade 3 or 4, tumor stage 2 any grade, or tumor stage 3A with grade 1 or 2 and no nodal metastases) or very-high risk for recurrence (tumor stage 3A with grade 3 or 4; tumor stage 3B, 3C, or 4 with any grade; or nodal metastases with any tumor stage or grade), as adapted from prior staging systems and clinical trials. 8,9Additional eligibility criteria are provided in the trial protocol (Supplement 1).

Intervention
Eligible patients were randomized 1:1 to receive either everolimus or placebo using a dynamic balancing algorithm with stratification based on risk group (intermediate high vs very high), histology (clear cell vs non-clear cell RCC), and Zubrod performance status (scored as 0 vs 1).Randomization procedures were conducted by the SWOG Statistics and Data Management Centre, and patients were randomly assigned on study registration through the NCI OPEN web-based application.
Participants, investigators, and those assessing outcomes were masked to group assignment.The study was double-blinded, with everolimus being administered (10 mg orally once daily) to the

Outcomes
To monitor for recurrence, patients underwent clinical evaluation (history and physical examinations), radiologic assessment (scans of the chest, abdomen, and pelvis) every 18 weeks in the first year, every 6 months in the next 2 years, and then annually thereafter until cancer recurrence, death, or a maximum of 10 years after randomization.Information on self-reported race and ethnicity was collected as part of the demographic data of the study participants.Race and ethnicity were classified as Asian, Black, White, Native American, Pacific Islander, multirace, and unknown.The primary end point was recurrence-free survival (RFS), defined as the time from randomization to first documented recurrence (local or distant) or death due to any cause, whichever event occurred first.Postrecurrence, the patients' treatment was unblinded to identify the next best treatments.Secondary end points included overall survival (OS).Survival was defined from the date of randomization to death from any cause.Data on adverse events for safety assessment were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 10

Statistical Analysis
Statistical analysis for the primary analysis has been published elsewhere. 7

Discussion
In this secondary analysis of an RCT, we report one of the largest non-clear cell RCC cohorts treated with an mTOR inhibitor, everolimus, after partial or radical nephrectomy.The role of everolimus is of particular interest in patients with chromophobe RCC.Mutations in mTOR, NRAS, TSC1, or TSC2 have been reported in approximately 23% of patients with chromophobe RCC, 10 suggesting possible therapeutic benefit from an mTOR inhibitor in this subset.2][13][14] In a subgroup of 16 patients with chromophobe RCC included in the phase 3 ASPEN study, there was no statistically significant benefit from everolimus (median PFS: 11.4 vs 5.5 months; HR. 0.7; 95% CI, 0.3-1.7). 16In another phase 2 single-group study that included 9 patients with chromophobe RCC, a disease control rate of 78% was reported with a combination of everolimus and lenvatinib. 13Similarly, everolimus has been shown to be clinically efficacious in patients with papillary

Limitations
This study has limitations.The subgroup analyses were not powered to test a difference, and there is a concern for false positives with multiple testing.The lack of a central pathology review to confirm non-clear cell histologies is also a shortcoming for this study.Nevertheless, EVEREST enrolled one of the largest cohorts of patients with papillary or chromophobe RCC in the adjuvant setting.Future biomarker analysis should enrich these data and help us elucidate the differences between these cohorts in greater depth.

Conclusions
This secondary analysis of the EVEREST RCT found that patients with papillary or chromophobe RCC did not benefit from treatment with everolimus in the adjuvant setting.Our study highlights an area of unmet need in the kidney cancer field.It thus serves to provide a foundational background for future RCTs to address specific subgroups of RCC for risk mitigation strategies in the adjuvant setting.
Subgroup analyses based on the 3 stratification factors, risk group (intermediate-high vs very high risk), histology (clear cell vs non-clear cell), and performance status (0 vs 1), were prespecified.The final analysis was performed in March 2022.For testing the hazard ratio (HR) for treatment effect, a Cox regression model was used for both OS and RFS.Due to the small sample sizes for the 2 subgroups, no additional covariates were included in the model.For RFS, recurrence or death was the event of interest.Censoring for both end points was the last contact date.To evaluate whether the treatment effect differed for clear cell vs papillary or chromophobe, all patients were included in the Cox model, and an indicator for histology (clear cell vs non-clear cell) and an interaction term for treatment with histology were placed in the model and evaluated with a residual χ 2 test.Kaplan-Meier curves were used to estimate OS and RFS distributions by treatment group.P values are reported as 2-sided, and significance was set at P Յ .044.Analyses were conducted using SAS software version 9.4 (SAS Institute).

Figure .
Figure.Kaplan-Meier Curves for Recurrence-Free Survival and Overall Survival in Patients with Papillary and Chromophobe Renal Cell Carcinoma (RCC)